Fluorine MR Imaging of Inflammation in Atherosclerotic Plaque in Vivo.

PURPOSE: To preliminarily test the hypothesis that fluorine 19 ((19)F) magnetic resonance (MR) imaging enables the noninvasive in vivo identification of plaque inflammation in a mouse model of atherosclerosis, with histologic findings as the reference standard. MATERIALS AND METHODS: The animal studies were approved by the local animal ethics committee. Perfluorocarbon (PFC) emulsions were injected intravenously in a mouse model of atherosclerosis (n = 13), after which (19)F and anatomic MR imaging were performed at the level of the thoracic aorta and its branches at 9.4 T. Four of these animals were imaged repeatedly (at 2-14 days) to determine the optimal detection time. Repeated-measures analysis of variance with a Tukey test was applied to determine if there was a significant change in (19)F signal-to-noise ratio (SNR) of the plaques and liver between the time points. Six animals were injected with a PFC emulsion that also contained a fluorophore. As a control against false-positive results, wild-type mice (n = 3) were injected with a PFC emulsion, and atherosclerotic mice were injected with a saline solution (n = 2). The animals were sacrificed after the last MR imaging examination, after which high-spatial-resolution ex vivo MR imaging and bright-field and immunofluorescent histologic examination were performed. RESULTS: (19)F MR signal was detected in vivo in plaques in the aortic arch and its branches. The SNR was found to significantly increase up to day 6 (P < .001), and the SNR of all mice at this time point was 13.4 ± 3.3. The presence of PFC and plaque in the excised vessels was then confirmed both through ex vivo (19)F MR imaging and histologic examination, while no signal was detected in the control animals. Immunofluorescent histologic findings confirmed the presence of PFC in plaque macrophages. CONCLUSION: (19)F MR imaging allows the noninvasive in vivo detection of inflammation in atherosclerotic plaques in a mouse model of atherosclerosis and opens up new avenues for both the early detection of vulnerable atherosclerosis and the elucidation of inflammation mechanisms in atherosclerosis.

Effects of Dietary Fat Oxidation Products and Flavonols on Lipoprotein Oxidation

Various studies suggest that oxidative modifications of low density lipoprotein (LDL), and also other lipoproteins, have an important role in the development of atherosclerosis. In addition to the oxidation products formed endogenously, oxidised triacylglycerols (TAG) and oxysterols in the diet contribute to the oxidised lipoproteins found in circulation. However, studies on both the effect of oxidised dietary lipids on lipoprotein lipid oxidation and the reactions that modify oxidised fat after ingestion have been scarce. Studies on the effects of dietary antioxidants on the lipid oxidation in vivo and the risk of atherosclerosis have been inconclusive. More clinical trials are needed to test the importance of lipoprotein oxidation as a cardiovascular risk factor in humans. In the recent years, various methods have been optimised and applied to the analysis of lipid oxidation products in vivo, and information on the molecular structures of oxidised lipids in plasma, lipoproteins and atherosclerotic plaques has started to accumulate. However, specific structures of oxidised TAG molecules present in these tissues and lipoprotein fractions have not been investigated earlier. In the orginal research in this thesis, an approach based on highperformance liquid chromatographyelectrospray ionisationmass spectrometry (HPLCESIMS) and baseline diene conjugation (BDC) methods was used in order to investigate lipid oxidation level and oxidised TAG molecular structures in pig and human lipoproteins after dietary interventions. The approach was optimised with human LDL samples, which contained various oxidation products of TAG. LDL particles of hyperlipidaemic subjects contained an elevated amount of conjugated dienes. In the pig studies, several oxidised TAG structures with hydroxy, keto, epoxy or aldehydic groups were found in chylomicrons and VLDL after diets rich in sunflower seed oil. Also, the results showed that oxidised sunflower seed oil increased the oxidation of lipoprotein lipids and their TAG molecules. TAG hydroperoxides could be detected neither in the small intestinal mucosa of the pigs fed on the oxidised oil nor in their chylomicrons or VLDL.6 In the clinical studies, dietary flavonol aglycones extracted from sea buckthorn berries did not have an effect on lipoprotein lipid oxidation and other potential risk factors of atherosclerosis, but their absorption was demonstrated. Oil supplementation seemed to increase the bioavailability of the flavonols. Oxidised TAG molecules were detected in LDL particles of the subjects after both flavonol and control diets.

Coronary vasomotor responses to isometric handgrip exercise are primarily mediated by nitric oxide: a noninvasive MRI test of coronary endothelial function.

Endothelial cell release of nitric oxide (NO) is a defining characteristic of nondiseased arteries, and abnormal endothelial NO release is both a marker of early atherosclerosis and a predictor of its progression and future events. Healthy coronaries respond to endothelial-dependent stressors with vasodilatation and increased coronary blood flow (CBF), but those with endothelial dysfunction respond with paradoxical vasoconstriction and reduced CBF. Recently, coronary MRI and isometric handgrip exercise (IHE) were reported to noninvasively quantify coronary endothelial function (CEF). However, it is not known whether the coronary response to IHE is actually mediated by NO and/or whether it is reproducible over weeks. To determine the contribution of NO, we studied the coronary response to IHE before and during infusion of N(G)-monomethyl-l-arginine (l-NMMA, 0.3 mg·kg(-1)·min(-1)), a NO-synthase inhibitor, in healthy volunteers. For reproducibility, we performed two MRI-IHE studies ∼8 wk apart in healthy subjects and patients with coronary artery disease (CAD). Changes from rest to IHE in coronary cross-sectional area (%CSA) and diastolic CBF (%CBF) were quantified. l-NMMA completely blocked normal coronary vasodilation during IHE [%CSA, 12.9 ± 2.5 (mean ± SE, placebo) vs. -0.3 ± 1.6% (l-NMMA); P < 0.001] and significantly blunted the increase in flow [%CBF, 47.7 ± 6.4 (placebo) vs. 10.6 ± 4.6% (l-NMMA); P < 0.001]. MRI-IHE measures obtained weeks apart strongly correlated for CSA (P < 0.0001) and CBF (P < 0.01). In conclusion, the normal human coronary vasoactive response to IHE is primarily mediated by NO. This noninvasive, reproducible MRI-IHE exam of NO-mediated CEF promises to be useful for studying CAD pathogenesis in low-risk populations and for evaluating translational strategies designed to alter CAD in patients.

Development of cardiovascular magnetic resonance imaging techniques for improved characterization of atherosclerotic disease

Atherosclerosis is a chronic cardiovascular disease that involves the thicken¬ing of the artery walls as well as the formation of plaques (lesions) causing the narrowing of the lumens, in vessels such as the aorta, the coronary and the carotid arteries. Magnetic resonance imaging (MRI) is a promising modality for the assessment of atherosclerosis, as it is a non-invasive and patient-friendly procedure that does not use ionizing radiation. MRI offers high soft tissue con¬trast already without the need of intravenous contrast media; while modifica¬tion of the MR pulse sequences allows for further adjustment of the contrast for specific diagnostic needs. As such, MRI can create angiographic images of the vessel lumens to assess stenoses at the late stage of the disease, as well as blood flow-suppressed images for the early investigation of the vessel wall and the characterization of the atherosclerotic plaques. However, despite the great technical progress that occurred over the past two decades, MRI is intrinsically a low sensitive technique and some limitations still exist in terms of accuracy and performance. A major challenge for coronary artery imaging is respiratory motion. State- of-the-art diaphragmatic navigators rely on an indirect measure of motion, per¬form a ID correction, and have long and unpredictable scan time. In response, self-navigation (SM) strategies have recently been introduced that offer 100% scan efficiency and increased ease of use. SN detects respiratory motion di¬rectly from the image data obtained at the level of the heart, and retrospectively corrects the same data before final image reconstruction. Thus, SN holds po-tential for multi-dimensional motion compensation. To this regard, this thesis presents novel SN methods that estimate 2D and 3D motion parameters from aliased sub-images that are obtained from the same raw data composing the final image. Combination of all corrected sub-images produces a final image with reduced motion artifacts for the visualization of the coronaries. The first study (section 2.2, 2D Self-Navigation with Compressed Sensing) consists of a method for 2D translational motion compensation. Here, the use of com- pressed sensing (CS) reconstruction is proposed and investigated to support motion detection by reducing aliasing artifacts. In healthy human subjects, CS demonstrated an improvement in motion detection accuracy with simula¬tions on in vivo data, while improved coronary artery visualization was demon¬strated on in vivo free-breathing acquisitions. However, the motion of the heart induced by respiration has been shown to occur in three dimensions and to be more complex than a simple translation. Therefore, the second study (section 2.3,3D Self-Navigation) consists of a method for 3D affine motion correction rather than 2D only. Here, different techniques were adopted to reduce background signal contribution in respiratory motion tracking, as this can be adversely affected by the static tissue that surrounds the heart. The proposed method demonstrated to improve conspicuity and vi¬sualization of coronary arteries in healthy and cardiovascular disease patient cohorts in comparison to a conventional ID SN method. In the third study (section 2.4, 3D Self-Navigation with Compressed Sensing), the same tracking methods were used to obtain sub-images sorted according to the respiratory position. Then, instead of motion correction, a compressed sensing reconstruction was performed on all sorted sub-image data. This process ex¬ploits the consistency of the sorted data to reduce aliasing artifacts such that the sub-image corresponding to the end-expiratory phase can directly be used to visualize the coronaries. In a healthy volunteer cohort, this strategy improved conspicuity and visualization of the coronary arteries when compared to a con¬ventional ID SN method. For the visualization of the vessel wall and atherosclerotic plaques, the state- of-the-art dual inversion recovery (DIR) technique is able to suppress the signal coming from flowing blood and provide positive wall-lumen contrast. How¬ever, optimal contrast may be difficult to obtain and is subject to RR variability. Furthermore, DIR imaging is time-inefficient and multislice acquisitions may lead to prolonged scanning times. In response and as a fourth study of this thesis (chapter 3, Vessel Wall MRI of the Carotid Arteries), a phase-sensitive DIR method has been implemented and tested in the carotid arteries of a healthy volunteer cohort. By exploiting the phase information of images acquired after DIR, the proposed phase-sensitive method enhances wall-lumen contrast while widens the window of opportunity for image acquisition. As a result, a 3-fold increase in volumetric coverage is obtained at no extra cost in scanning time, while image quality is improved. In conclusion, this thesis presented novel methods to address some of the main challenges for MRI of atherosclerosis: the suppression of motion and flow artifacts for improved visualization of vessel lumens, walls and plaques. Such methods showed to significantly improve image quality in human healthy sub¬jects, as well as scan efficiency and ease-of-use of MRI. Extensive validation is now warranted in patient populations to ascertain their diagnostic perfor¬mance. Eventually, these methods may bring the use of atherosclerosis MRI closer to the clinical practice. Résumé L'athérosclérose est une maladie cardiovasculaire chronique qui implique le épaississement de la paroi des artères, ainsi que la formation de plaques (lé¬sions) provoquant le rétrécissement des lumières, dans des vaisseaux tels que l'aorte, les coronaires et les artères carotides. L'imagerie par résonance magné¬tique (IRM) est une modalité prometteuse pour l'évaluation de l'athérosclérose, car il s'agit d'une procédure non-invasive et conviviale pour les patients, qui n'utilise pas des rayonnements ionisants. L'IRM offre un contraste des tissus mous très élevé sans avoir besoin de médias de contraste intraveineux, tan¬dis que la modification des séquences d'impulsions de RM permet en outre le réglage du contraste pour des besoins diagnostiques spécifiques. À ce titre, l'IRM peut créer des images angiographiques des lumières des vaisseaux pour évaluer les sténoses à la fin du stade de la maladie, ainsi que des images avec suppression du flux sanguin pour une première enquête des parois des vais¬seaux et une caractérisation des plaques d'athérosclérose. Cependant, malgré les grands progrès techniques qui ont eu lieu au cours des deux dernières dé¬cennies, l'IRM est une technique peu sensible et certaines limitations existent encore en termes de précision et de performance. Un des principaux défis pour l'imagerie de l'artère coronaire est le mou¬vement respiratoire. Les navigateurs diaphragmatiques de pointe comptent sur une mesure indirecte de mouvement, effectuent une correction 1D, et ont un temps d'acquisition long et imprévisible. En réponse, les stratégies d'auto- navigation (self-navigation: SN) ont été introduites récemment et offrent 100% d'efficacité d'acquisition et une meilleure facilité d'utilisation. Les SN détectent le mouvement respiratoire directement à partir des données brutes de l'image obtenue au niveau du coeur, et rétrospectivement corrigent ces mêmes données avant la reconstruction finale de l'image. Ainsi, les SN détiennent un poten¬tiel pour une compensation multidimensionnelle du mouvement. A cet égard, cette thèse présente de nouvelles méthodes SN qui estiment les paramètres de mouvement 2D et 3D à partir de sous-images qui sont obtenues à partir des mêmes données brutes qui composent l'image finale. La combinaison de toutes les sous-images corrigées produit une image finale pour la visualisation des coronaires ou les artefacts du mouvement sont réduits. La première étude (section 2.2,2D Self-Navigation with Compressed Sensing) traite d'une méthode pour une compensation 2D de mouvement de translation. Ici, on étudie l'utilisation de la reconstruction d'acquisition comprimée (compressed sensing: CS) pour soutenir la détection de mouvement en réduisant les artefacts de sous-échantillonnage. Chez des sujets humains sains, CS a démontré une amélioration de la précision de la détection de mouvement avec des simula¬tions sur des données in vivo, tandis que la visualisation de l'artère coronaire sur des acquisitions de respiration libre in vivo a aussi été améliorée. Pourtant, le mouvement du coeur induite par la respiration se produit en trois dimensions et il est plus complexe qu'un simple déplacement. Par conséquent, la deuxième étude (section 2.3, 3D Self-Navigation) traite d'une méthode de cor¬rection du mouvement 3D plutôt que 2D uniquement. Ici, différentes tech¬niques ont été adoptées pour réduire la contribution du signal du fond dans le suivi de mouvement respiratoire, qui peut être influencé négativement par le tissu statique qui entoure le coeur. La méthode proposée a démontré une amélioration, par rapport à la procédure classique SN de correction 1D, de la visualisation des artères coronaires dans le groupe de sujets sains et des pa¬tients avec maladies cardio-vasculaires. Dans la troisième étude (section 2.4,3D Self-Navigation with Compressed Sensing), les mêmes méthodes de suivi ont été utilisées pour obtenir des sous-images triées selon la position respiratoire. Au lieu de la correction du mouvement, une reconstruction de CS a été réalisée sur toutes les sous-images triées. Cette procédure exploite la cohérence des données pour réduire les artefacts de sous- échantillonnage de telle sorte que la sous-image correspondant à la phase de fin d'expiration peut directement être utilisée pour visualiser les coronaires. Dans un échantillon de volontaires en bonne santé, cette stratégie a amélioré la netteté et la visualisation des artères coronaires par rapport à une méthode classique SN ID. Pour la visualisation des parois des vaisseaux et de plaques d'athérosclérose, la technique de pointe avec double récupération d'inversion (DIR) est capa¬ble de supprimer le signal provenant du sang et de fournir un contraste posi¬tif entre la paroi et la lumière. Pourtant, il est difficile d'obtenir un contraste optimal car cela est soumis à la variabilité du rythme cardiaque. Par ailleurs, l'imagerie DIR est inefficace du point de vue du temps et les acquisitions "mul- tislice" peuvent conduire à des temps de scan prolongés. En réponse à ce prob¬lème et comme quatrième étude de cette thèse (chapitre 3, Vessel Wall MRI of the Carotid Arteries), une méthode de DIR phase-sensitive a été implémenté et testé

Obese, smoker, and obese smoker : is there a general lifestyle gradient?

Aim: Obesity and smoking are major CVD risk factors and may be associated with other unfavourable lifestyle behaviours. Our aim was to investigate the significance of obesity, heavy smoking, and both combined in terms of prevalence trends and their relationship with other lifestyle factors. Methods: We used data from the population-based cross-sectional Swiss Health Survey (5 waves, 1992-2012) comprising 85,575 individuals aged 18 years. Height, weight, and smoking status were self-reported. We used multinomial logistic regression to analyse differences in lifestyle for the combinations of BMI category and smoking status, focusing on obese and heavy smokers. We defined normal-weight never smokers as reference.

Multiplicative interaction of functional inflammasome genetic variants in determining the risk of gout.

INTRODUCTION: The acute gout flare results from a localised self-limiting innate immune response to monosodium urate (MSU) crystals deposited in joints in hyperuricaemic individuals. Activation of the caspase recruitment domain-containing protein 8 (CARD8) NOD-like receptor pyrin-containing 3 (NLRP3) inflammasome by MSU crystals and production of mature interleukin-1β (IL-1β) is central to acute gouty arthritis. However very little is known about genetic control of the innate immune response involved in acute gouty arthritis. Therefore our aim was to test functional single nucleotide polymorphism (SNP) variants in the toll-like receptor (TLR)-inflammasome-IL-1β axis for association with gout. METHODS: 1,494 gout cases of European and 863 gout cases of New Zealand (NZ) Polynesian (Māori and Pacific Island) ancestry were included. Gout was diagnosed by the 1977 ARA gout classification criteria. There were 1,030 Polynesian controls and 10,942 European controls including from the publicly-available Atherosclerosis Risk in Communities (ARIC) and Framingham Heart (FHS) studies. The ten SNPs were either genotyped by Sequenom MassArray or by Affymetrix SNP array or imputed in the ARIC and FHS datasets. Allelic association was done by logistic regression adjusting by age and sex with European and Polynesian data combined by meta-analysis. Sample sets were pooled for multiplicative interaction analysis, which was also adjusted by sample set. RESULTS: Eleven SNPs were tested in the TLR2, CD14, IL1B, CARD8, NLRP3, MYD88, P2RX7, DAPK1 and TNXIP genes. Nominally significant (P < 0.05) associations with gout were detected at CARD8 rs2043211 (OR = 1.12, P = 0.007), IL1B rs1143623 (OR = 1.10, P = 0.020) and CD14 rs2569190 (OR = 1.08; P = 0.036). There was significant multiplicative interaction between CARD8 and IL1B (P = 0.005), with the IL1B risk genotype amplifying the risk effect of CARD8. CONCLUSION: There is evidence for association of gout with functional variants in CARD8, IL1B and CD14. The gout-associated allele of IL1B increases expression of IL-1β - the multiplicative interaction with CARD8 would be consistent with a synergy of greater inflammasome activity (resulting from reduced CARD8) combined with higher levels of pre-IL-1β expression leading to increased production of mature IL-1β in gout.

FOXC2 and fluid shear stress stabilize postnatal lymphatic vasculature.

Biomechanical forces, such as fluid shear stress, govern multiple aspects of endothelial cell biology. In blood vessels, disturbed flow is associated with vascular diseases, such as atherosclerosis, and promotes endothelial cell proliferation and apoptosis. Here, we identified an important role for disturbed flow in lymphatic vessels, in which it cooperates with the transcription factor FOXC2 to ensure lifelong stability of the lymphatic vasculature. In cultured lymphatic endothelial cells, FOXC2 inactivation conferred abnormal shear stress sensing, promoting junction disassembly and entry into the cell cycle. Loss of FOXC2-dependent quiescence was mediated by the Hippo pathway transcriptional coactivator TAZ and, ultimately, led to cell death. In murine models, inducible deletion of Foxc2 within the lymphatic vasculature led to cell-cell junction defects, regression of valves, and focal vascular lumen collapse, which triggered generalized lymphatic vascular dysfunction and lethality. Together, our work describes a fundamental mechanism by which FOXC2 and oscillatory shear stress maintain lymphatic endothelial cell quiescence through intercellular junction and cytoskeleton stabilization and provides an essential link between biomechanical forces and endothelial cell identity that is necessary for postnatal vessel homeostasis. As FOXC2 is mutated in lymphedema-distichiasis syndrome, our data also underscore the role of impaired mechanotransduction in the pathology of this hereditary human disease.

Effect of cocoa powder in the prevention of cardiovascular disease: biological, consumption and inflammatory biomarkers. A metabolomic approach

Numerous health benefits have been attributed to cocoa and its derived products in the last decade including antioxidant, anti-platelet and positive effects on lipid metabolism and vascular function. Inflammation plays a key role in the initiation and progression of atherosclerosis. However, cocoa feeding trials focused on inflammation are still rare and the results yielded are controversial. Health effects derived from cocoa consumption have been partly attributed to its polyphenol content, in particular of flavanols. Bioavailability is a key issue for cocoa polyphenols in order to be able to exert their biological activities. In the case of flavanols, bioavailability is strongly influenced by several factors, such as their degree of polymerization and the food matrix in which the polyphenols are delivered. Furthermore, gut has become an active site for the metabolism of procyanidins (oligomeric and polymeric flavanols). Estimation of polyphenol consumption or exposure is also a very challenging task in Food and Nutrition Science in order to correlate the intake of phytochemicals with in vivo health effects. In the area of nutrition, modern analytical techniques based on mass spectrometry are leading to considerable advances in targeted metabolite analysis and particularly in Metabolomics or global metabolite analysis. In this chapter we have summarized the most relevant results of our recent research on the bioavailability of cocoa polyphenols in humans and the effect of the matrix in which cocoa polyphenols are delivered considering both targeted analysis and a metabolomic approach. Furthermore, we have also summarized the effect of long-term consumption of cocoa powder in patients at high risk of cardiovascular disease (CVD) on the inflammatory biomarkers of atherosclerosis.

Home Blood Pressure Measurement – Epidemiology and Clinical Application

Verenpaineen kotimittaus − epidemiologia ja kliininen käyttö Kohonnutta verenpainetta, maailmanlaajuisesti merkittävintä ennenaikaiselle kuolemalle altistavaa riskitekijää, ei voida tunnistaa tai hoitaa ilman tarkkoja ja käytännöllisiä verenpaineen mittausmenetelmiä. Verenpaineen kotimittaus on saavuttanut suuren suosion potilaiden keskuudessa. Lääkärit eivät ole kuitenkaan vielä täysin hyväksyneet verenpaineen kotimittausta, sillä riittävä todistusaineisto sen toimivuudesta ja eduista on puuttunut. Tämän tutkimuksen tarkoituksena oli osoittaa, että kotona mitattu verenpaine (kotipaine) on perinteistä vastaanotolla mitattua verenpainetta (vastaanottopaine) tarkempi, ja että se on tehokas myös kliinisessä käytössä. Tutkimme kotipaineen käyttöä verenpainetaudin diagnosoinnissa ja hoidossa. Lisäksi tarkastelimme kotipaineen yhteyttä verenpainetaudin aiheuttamiin kohde-elinvaurioihin. Ensimmäinen aineisto, joka oli edustava otos Suomen aikuisväestöstä, koostui 2 120 45–74-vuotiaasta tutkimushenkilöstä. Tutkittavat mittasivat kotipainettaan viikon ajan ja osallistuivat terveystarkastukseen, johon sisältyi kliinisen tutkimuksen ja haastattelun lisäksi sydänfilmin otto ja vastaanottopaineen mittaus. 758 tutkittavalle suoritettiin lisäksi kaulavaltimon seinämän intima-mediakerroksen paksuuden (valtimonkovettumataudin mittari) mittaus ja 237:lle valtimon pulssiaallon nopeuden (valtimojäykkyyden mittari) mittaus. Toisessa aineistossa, joka koostui 98 verenpainetautia sairastavasta potilaasta, hoitoa ohjattiin satunnaistamisesta riippuen joko ambulatorisen eli vuorokausirekisteröinnillä mitatun verenpaineen tai kotipaineen perusteella. Vastaanottopaine oli kotipainetta merkittävästi korkeampi (systolisen/diastolisen paineen keskiarvoero oli 8/3 mmHg) ja yksimielisyys verenpainetaudin diagnoosissa kahden menetelmän välillä oli korkeintaan kohtalainen (75 %). 593 tutkittavasta, joilla oli kohonnut verenpaine vastaanotolla, 38 %:lla oli normaali verenpaine kotona eli ns. valkotakkiverenpaine. Verenpainetauti voidaan siis ylidiagnosoida joka kolmannella potilaalla seulontatilanteessa. Valkotakkiverenpaine oli yhteydessä lievästi kohonneeseen verenpaineeseen, matalaan painoindeksiin ja tupakoimattomuuteen, muttei psykiatriseen sairastavuuteen. Valkotakkiverenpaine ei kuitenkaan vaikuttaisi olevan täysin vaaraton ilmiö ja voi ennustaa tulevaa verenpainetautia, sillä siitä kärsivien sydän- ja verisuonitautien riskitekijäprofiili oli normaalipaineisten ja todellisten verenpainetautisten riskitekijäprofiilien välissä. Kotipaineella oli vastaanottopainetta vahvempi yhteys verenpainetaudin aiheuttamiin kohde-elinvaurioihin (intima-mediakerroksen paksuus, pulssiaallon nopeus ja sydänfilmistä todettu vasemman kammion suureneminen). Kotipaine oli tehokas verenpainetaudin hoidon ohjaaja, sillä kotipaineeseen ja ambulatoriseen paineeseen, jota on pidetty verenpainemittauksen ”kultaisena standardina”, perustuva lääkehoidon ohjaus johti yhtä hyvään verenpaineen hallintaan. Tämän ja aikaisempien tutkimusten tulosten pohjalta voidaan todeta, että verenpaineen kotimittaus on selkeä parannus perinteiseen vastaanotolla tapahtuvaan verenpainemittaukseen verrattuna. Verenpaineen kotimittaus on käytännöllinen, tarkka ja laajasti saatavilla oleva menetelmä, josta voi tulla jopa ensisijainen vaihtoehto verenpainetautia diagnosoitaessa ja hoitaessa. Verenpaineen mittauskäytäntöön tarvitaan muutos, sillä näyttöön perustuvan lääketieteen perusteella vaikuttaa, että vastaanotolla tapahtuvaa verenpainemittausta tulisi käyttää vain seulontatarkoitukseen.

Grande fréquence des prescriptions médicamenteuses à visée cardiovasculaire potentiellement inappropriées dans la population âgée [Potentially inappropriate prescribing cardiovascular medications in the aged population: prospective study in a district hospital centre (France)].

OBJECTIVES: Cardiovascular disease is a leading cause of morbidity and mortality in the elderly population. We evaluated the adequacy of prescribing (miss and under used) with respect to STOPP-START criteria. METHODS: A sample of 100 patients hospitalized in cardiovascular specialty divisions (medicine or surgery) or in the different sectors making up the geriatric network (day-care hospital, short or rehabilitation ward, nursing home) has been considered. Drug prescriptions at the admission time were analysed. RESULTS: Eight hundred and seventy-four prescriptions were analysed. In 65% of patients, from 5 to 10 medications were prescribed and in 28% over 10. Fifty-four percent of patients had, at least, one potentially inappropriate prescription (PIP) by STOPP. Among them, 48% of PIP prescriptions contained 1, 41% 2 and 11% 3 or more. The omission of one medication according to START criteria concerned 57% of the sample. Among them, 46% had one omission, 44% 2 to 3 and 10% 4 omissions or over. The cardiovascular system is the one most concerned by the PIP. Whether 28.1% of the PIP by STOPP criteria concerned cardiovascular drugs, the omission of prescription, according to START criteria, was 41.8%. There was no significant difference between the different settings studied. There was no effect of age or sex on the impact of PIP (P>0.20) or being polymédiqué (P=0.44). According to the criteria STOPP-A, the prescription of antiplatelet (indication and dose) was highlighted. Prescribing omission also concerned antiplatelet agents but also statins in patients with atherosclerosis as well as antiplatelet and anticoagulant in patients with permanent atrial fibrillation and inhibitor of angiotensin converting enzyme (ACE) after myocardial infarction or with chronic heart failure. CONCLUSION: Potentially inappropriate prescribing medications were very common in elderly patients with cardiovascular conditions. They concerned as much as underusing of important drugs with potential benefits and prescribing commission of treatment that did not fit with patients' comorbidities and/or characteristics.

Effect of cocoa powder on the modulation of inflammatory biomarkers in patients at high risk of cardiovascular disease

Background: Epidemiologic studies have suggested that flavonoid intake plays a critical role in the prevention of coronary heart disease. Because atherosclerosis is considered a low-grade inflammatory disease, some feeding trials have analyzed the effects of cocoa (an important source of flavonoids) on inflammatory biomarkers, but the results have been controversial. Objective: The objective was to evaluate the effects of chronic cocoa consumption on cellular and serum biomarkers related to atherosclerosis in high-risk patients. Design: Forty-two high-risk volunteers (19 men and 23 women; mean 6 SD age: 69.7 6 11.5 y) were included in a randomized crossover feeding trial. All subjects received 40 g cocoa powder with 500 mL skim milk/d (C+M) or only 500 mL skim milk/d (M) for 4 wk. Before and after each intervention period, cellular and serum inflammatory biomarkers related to atherosclerosis were evaluated. Results: Adherence to the dietary protocol was excellent. No significant changes in the expression of adhesion molecules on T lymphocyte surfaces were found between the C+M and M groups. However, in monocytes, the expression of VLA-4, CD40, and CD36 was significantly lower (P = 0.005, 0.028, and 0.001, respectively) after C+M intake than after M intake. In addition, serum concentrations of the soluble endothelium-derived adhesion molecules P-selectin and intercellular adhesion molecule-1 were significantly lower (both P = 0.007) after C+M intake than after M intake. Conclusions: These results suggest that the intake of cocoa polyphenols may modulate inflammatory mediators in patients at high risk of cardiovascular disease. These antiinflammatory effects may contribute to the overall benefits of cocoa consumption against atherosclerosis. This trial was registered in the Current Controlled Trials at London, International Standard Randomized Controlled Trial Number, at controlled-trials.com as ISRCTN75176807.

Association between parental history and genetic risk scores for coronary heart disease prediction: The population-based CoLaus study.

BACKGROUND AND AIMS: Parental history (PH) and genetic risk scores (GRSs) are separately associated with coronary heart disease (CHD), but evidence regarding their combined effects is lacking. We aimed to evaluate the joint associations and predictive ability of PH and GRSs for incident CHD. METHODS: Data for 4283 Caucasians were obtained from the population-based CoLaus Study, over median follow-up time of 5.6 years. CHD was defined as incident myocardial infarction, angina, percutaneous coronary revascularization or bypass grafting. Single nucleotide polymorphisms for CHD identified by genome-wide association studies were used to construct unweighted and weighted versions of three GRSs, comprising of 38, 53 and 153 SNPs respectively. RESULTS: PH was associated with higher values of all weighted GRSs. After adjustment for age, sex, smoking, diabetes, systolic blood pressure, low and high density lipoprotein cholesterol, PH was significantly associated with CHD [HR 2.61, 95% CI (1.47-4.66)] and further adjustment for GRSs did not change this estimate. Similarly, one standard deviation change of the weighted 153-SNPs GRS was significantly associated with CHD [HR 1.50, 95% CI (1.26-1.80)] and remained so, after further adjustment for PH. The weighted, 153-SNPs GRS, but not PH, modestly improved discrimination [(C-index improvement, 0.016), p = 0.048] and reclassification [(NRI improvement, 8.6%), p = 0.027] beyond cardiovascular risk factors. After including both the GRS and PH, model performance improved further [(C-index improvement, 0.022), p = 0.006]. CONCLUSION: After adjustment for cardiovascular risk factors, PH and a weighted, polygenic GRS were jointly associated with CHD and provided additive information for coronary events prediction.

Five year trends in dyslipidaemia prevalence and management in Switzerland: The CoLaus study.

BACKGROUND AND AIMS: Data from prospective cohorts describing dyslipidaemia prevalence and treatment trends are lacking. Using data from the prospective CoLaus study, we aimed to examine changes in serum lipid levels, dyslipidaemia prevalence and management in a population-based sample of Swiss adults. METHODS AND RESULTS: Cardiovascular risk was assessed using PROCAM. Dyslipidaemia and low-density lipoprotein cholesterol (LDL-C) target levels were defined according to the Swiss Group for Lipids and Atherosclerosis. Complete baseline and follow up (FU) data were available for n = 4863 subjects during mean FU time of 5.6 years. Overall, 32.1% of participants were dyslipidaemic at baseline vs 46.3% at FU (p < 0.001). During this time, lipid lowering medication (LLM) rates among dyslipidaemic subjects increased from 34.0% to 39.2% (p < 0.001). In secondary prevention, LLM rates were 42.7% at baseline and 53.2% at FU (p = 0.004). In multivariate analysis, LLM use among dyslipidaemic subjects, between baseline and FU, was positively associated with personal history of CVD, older age, hypertension, higher BMI and diabetes, while negatively associated with higher educational level. Among treated subjects, LDL-C target achievement was positively associated with diabetes and negatively associated with personal history of CVD and higher BMI. Among subjects treated at baseline, LLM discontinuation was negatively associated with older age, male sex, smoking, hypertension and parental history of CVD. CONCLUSIONS: In Switzerland, the increase over time in dyslipidaemia prevalence was not paralleled by a similar increase in LLM. In a real-life setting, dyslipidaemia management remains far from optimal, both in primary and secondary prevention.

Prevention of vascular dysfunction and arterial hypertension in mice generated by assisted reproductive technologies by addition of melatonin to culture media.

Assisted reproductive technologies (ART) induce vascular dysfunction in humans and mice. In mice, ART-induced vascular dysfunction is related to epigenetic alteration of the endothelial nitric oxide synthase (eNOS) gene, resulting in decreased vascular eNOS expression and nitrite/nitrate synthesis. Melatonin is involved in epigenetic regulation, and its administration to sterile women improves the success rate of ART. We hypothesized that addition of melatonin to culture media may prevent ART-induced epigenetic and cardiovascular alterations in mice. We, therefore, assessed mesenteric-artery responses to acetylcholine and arterial blood pressure, together with DNA methylation of the eNOS gene promoter in vascular tissue and nitric oxide plasma concentration in 12-wk-old ART mice generated with and without addition of melatonin to culture media and in control mice. As expected, acetylcholine-induced mesenteric-artery dilation was impaired (P = 0.008 vs. control) and mean arterial blood pressure increased (109.5 ± 3.8 vs. 104.0 ± 4.7 mmHg, P = 0.002, ART vs. control) in ART compared with control mice. These alterations were associated with altered DNA methylation of the eNOS gene promoter (P < 0.001 vs. control) and decreased plasma nitric oxide concentration (10.1 ± 11.1 vs. 29.5 ± 8.0 μM) (P < 0.001 ART vs. control). Addition of melatonin (10(-6) M) to culture media prevented eNOS dysmethylation (P = 0.005, vs. ART + vehicle), normalized nitric oxide plasma concentration (23.1 ± 14.6 μM, P = 0.002 vs. ART + vehicle) and mesentery-artery responsiveness to acetylcholine (P < 0.008 vs. ART + vehicle), and prevented arterial hypertension (104.6 ± 3.4 mmHg, P < 0.003 vs. ART + vehicle). These findings provide proof of principle that modification of culture media prevents ART-induced vascular dysfunction. We speculate that this approach will also allow preventing ART-induced premature atherosclerosis in humans.

Intracellular ATP Decrease Mediates NLRP3 Inflammasome Activation upon Nigericin and Crystal Stimulation.

Activation of the nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome initiates an inflammatory response, which is associated with host defense against pathogens and the progression of chronic inflammatory diseases such as gout and atherosclerosis. The NLRP3 inflammasome mediates caspase-1 activation and subsequent IL-1β processing in response to various stimuli, including extracellular ATP, although the roles of intracellular ATP (iATP) in NLRP3 activation remain unclear. In this study, we found that in activated macrophages artificial reduction of iATP by 2-deoxyglucose, a glycolysis inhibitor, caused mitochondrial membrane depolarization, leading to IL-1β secretion via NLRP3 and caspase-1 activation. Additionally, the NLRP3 activators nigericin and monosodium urate crystals lowered iATP through K(+)- and Ca(2+)-mediated mitochondrial dysfunction, suggesting a feedback loop between iATP loss and lowering of mitochondrial membrane potential. These results demonstrate the fundamental roles of iATP in the maintenance of mitochondrial function and regulation of IL-1β secretion, and they suggest that maintenance of the intracellular ATP pools could be a strategy for countering NLRP3-mediated inflammation.